Parkinson's disease (PD) is a progressive neurological disorder, characterized by degeneration of dopamine neurons and their nerve terminals from specific brain areas, particularly the caudate and putamen. Since dopamine neurons contain the dopamine transporter, the degenerative process can be monitored by the loss of the transporter in presynaptic nerve fibers and terminals. Radioligands that bind to these sites represent promising probes for the diagnosis and for monitoring disease progression. We developed a novel SPECT imaging agent, [123I]2 -carbomethoxy-3 -(4-fluorophenyl)-N-(1-iodoprop-1-en-3-yl)nortropane ([123I] altropane) that displays favorable binding characteristics. The MPTP model of Parkinsonism was used to evaluate the probe. Three rhesus monkeys were imaged prior to and at 1 and 2 months after treatment with MPTP (0.6 mg/kg administered 3 times within 10 days). The SPECT results were correlated with scores of motor behavior and compared with PET imaging using [11C]2 -carbomethoxy-3 -aryltropane ([11C]-CFT) or [11C] WIN 35,428. In normal animals, striatal accumulation of radioactivity was rapid and peak levels were achieved within 30 min. after injection. Striatal accumulation of [123I]-altropane was nearly fully displaceable with the dopamine transport inhibitor WIN 35,428 (1 mg/kg) but was not affected by a similar dose of the serotonin transport inhibitor citalopram. The striatal to cerebellar ratio measured at 30 min. after injection of [123I] altropane was significantly higher (p < 0.01) than with [11C]-WIN 35,428; > 10:1 vs ~ 5:1. After MPTP treatment, this ratio decreased to 1:1 with [123I] altropane and 1.5:1 with [11C]-WIN 35,428. These results demonstrate that [123I] altropane is the first SPECT ligand for dopamine transporter sites that combine the critical characteristics of (1) high striatal to cerebellar ratios; (2) high selectivity for dopamine vs. serotonin binding sites; (3) convenient preparation at high specific activity and radiochemical purity and (4)